for hepatocellular carcinoma
"
Julio C Hernández
1, Marcia Samada
1, Alejandro Roque
1, Yolanda Cruz
2,
Ivón Howland
2, Irma Fernández
31Grupo de Hepatología 2Laboratorio Clínico 3Bioestadística
Centro de Investigaciones Médico Quirúrgicas, CIMEQ Calle 216 y 11B, Reparto Siboney, Playa, CP 12100, La Habana, Cuba E-mail: [email protected]
ABSTRACT
Hepatocellular carcinoma (HCC) variously occupies the fifth or sixth position as the most frequent neoplasia worldwi-de. The present work used alpha-fetoprotein (AFP) determinations on the ultra-micro analytical system (SUMA®) as a tumoral marker in 189 cirrhotic patients evaluated at the Center for Medical and Surgical Research between January 1999 and September 2005. The principal factors associated to increases in AFP were HCC and viral cirrhosis. In all, 22 patients (11.64%) suffered from HCC, with viral cirrhosis caused mainly by hepatitis C virus infections as the most important etiological factor. AFP as a tumoral marker displayed a sensitivity of 68.18% and a specificity of 92.17%, which increased to 86.36 and 100% respectively when combined with abdominal sonography. It is concluded that AFP is valuable for the diagnosis of HCC.
Keywords: hepatocelular carcinoma, cirrhosis, alpha-fetoprotein
Biotecnología Aplicada 2011;28:34-39
RESUMEN
Valor diagnóstico de la alfa-fetoproteína en el carcinoma hepatocelular. El carcinoma hepatocelular (CHC) es la quinta y sexta neoplasia más frecuente en el mundo. En este trabajo se empleó la alfa-fetoproteína (AFP) por la técnica del sistema ultramicroanalítico (SUMA®), como marcador tumoral en 189 pacientes cirróticos evaluados en el Centro de Investigaciones Médico-Quirúrgicas (CIMEQ), entre enero de 1999 y septiembre de 2005. Los principales factores que se asociaron a una elevación de la AFP fueron el CHC y la cirrosis viral. Veintidós enfermos presentaron CHC (11.64%) y la causa más importante fue la cirrosis hepática viral, principalmente por el virus de la hepatitis C. Este marcador tumoral mostró una sensibilidad de 68.18% y una especificidad de 92.17%. Al combinarlo con la ecografía abdominal, se incrementó la sensibilidad a 86.36% y la especificidad a 100%. Se concluyó que la AFP tuvo valor en el diagnóstico del CHC.
Palabras clave: carcinoma hepatocelular, cirrosis, alfa-fetoproteína
I
ntroduction
Hepatocellular carcinoma (HCC) is a malignant tumor of epithelial origin derived from parenchymal cells of the liver. According to the available statistical data, it is the main cause of death in people with compen-sated hepatic cirrhosis (HC), and variously alternates between the fi fth and sixth position, according to the country, as the most frequent neoplasia (500 000 to 700 000 new cases worldwide per year). In addition, it has very low annual survival rates (3 to 5%), and is considered to be the third most deadly cancer [1, 2].
The diagnosis of HCC is often based on screening and surveillance strategies whose mainstays are the use of imagenological techniques and the measure-ment of the levels of serum alpha-fetoprotein (AFP) [3-5].
AFP is a 72 kDa onco-fetal glycoprotein with a size of 591 aminoacids [6]. It is normally synthesized during fetal life, fi rst in the yolk sac and then in fetal liver; its synthesis is normally repressed in adults [7]. High levels of AFP are observed during adulthood only under certain conditions, such as pregnancy, the presence of some neoplasias (e.g. HCC, gastric
carci-noma, testicular carcicarci-noma, lung cancer and
pancrea-RESEARCH
tic cancer) and some non-neoplastic disorders such as HC and chronic hepatitis [8].
The association between serum AFP and HCC has been widely examined and described by a large num-ber of groups [9]. Regardless, its sensitivity and spe-cifi city for diagnosing HCC are variable, with fi gures ranging from 39 to 73% and 65 to 96%, respectively [3, 10-29], depending on factors such as the specifi c assay used, the design of the study, the characteristics of the study population, and the designated cut-off le-vel [20].
A new liver transplantation (LT) program began to be implemented and developed at the Center for Me-dical and Surgical Research (CIMEQ) starting from 1998, a necessary part of which was the evaluation of cirrhotic patients in order to discard the presence of HCC. In order to reach this objective, a screening and surveillance strategy was followed, based on the de-termination of serum AFP with the Cuban ultra-micro analytical system SUMA®.
Therefore, a study was designed aimed at the iden-tifi cation of the factors associated to increased le-vels of serum AFP in the target population (cirrhotic
1. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. 2005;55:74-108.
2. El-Serag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology. 2007; 132:2557-76.
3. Trevisani F, D’Intino PE, Morselli-Labate AM, Mazzella G, Accogli E, Caraceni P, et al. Serum alpha-fetoprotein for diagnosis of hepatocellular carcinoma in patients with chronic liver disease: influence of HBsAg and anti-HCV status. J Hepatol. 2001;34:570-5.
4. Beale G, Chattopadhyay D, Gray J, Stewart S, Hudson M, Day C, et al. AFP, PIVKAII, GP3, SCCA-1 and follisatin as surveillance biomarkers for hepatocellular cancer in non-alcoholic and alcoholic fatty liver disease. BMC Cancer. 2008;8:200.
5. Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology. 2005;42:1208-36.
paients). The study was also designed to measure the sensitivity and specifi city of AFP for the diagnosis of HCC in HC patients.
M
aterials and methods
This was a descriptive, prospective and longitudinal study that took place at CIMEQ from January 1999 to September 2005. A total of 191 patients with HC of varying etiologies were evaluated and treated by the group specialized in liver transplantation (LT). The exclusion criteria were pregnancy, antecedents of other neoplasias and refusal of the patient to enter the study. Only two prospective patients were eliminated due to previous neoplasias.
The data gathered for the investigation were ob-tained through the clinical evaluation of the patients using direct interviews, physical examinations, and the results of complementary studies contained in their medical records. A diagnosis of HC was established by compliance with at least one of the following cri-teria: histology, laparoscopy, and unequivocal clinical signs of the disease, provided mainly by the physical exam, the imagenological elements of the sonograms and the results of the upper GI endoscopy.
The HCC diagnosis took into account the criteria established by the European Association for the Study of Liver Disease (EASLD)for patients with HC and tumoral lesions larger than 2 cm, which produce a ty-pical pattern of hypervascularization for imagenologi-cal techniques [11].
The reference values for serum AFP established by the Immunoassay Center using the SUMA® platform
were used throughout this work. Although the labora-tory facilities at CIMEQ produce AFP results in UI/mL they were converted to ng/mL (conversion factor: 1 UI/mL = 1.24 ng/mL) to guarantee uniformity in the discussion of the work. A test was considered normal if AFP concentration was below 15 UI/mL (i.e. lower than 18.60 ng/mL). The patients were fasted prior to the collection of the blood samples, which were processed by UMELISA®AFP (immunoenzyme assay used for
the quantitative determination of alpha-fetoprotein in human serum and amniotic fl uid) at the SUMA®
labo-ratory of the Clinical Department from CIMEQ. The AFP determinations were performed during the
fi rst evaluation visit of the patient, and then every 6 months. The serum level of AFP related to the diagno-sis, was corresponded with the fi rst value of this tumo-ral marker at the moment of diagnosis of the disease.
The data were processed with the statistical soft-ware package Statistical Package for the Social Scien-ces (SPSS) version 13.0 and with Epidat version 3.1, an informatics tool for the epidemiological analysis of tabulated data. Mean value, standard deviation (SD) and median were computed for all quantitative varia-bles; using percentages instead for qualitative parame-ters. Sensitivity, specifi city, positive predictive values (PPV) and negative predictive values (NPV) were also calculated and used to estimate Youden’s index.
The comparison of variables in categories was performed using chi-squared and Fisher’s exact pro-bability tests. Mann-Whitney’s U test or the Kruskal Wallis test was used when comparing quantitative va-riables between two or more independent groups, res-pectively. The Tamhane test was used for statistically
signifi cant differences.
The calculation of the sensitivity and specifi city reached when using different serum AFP thresholds for the diagnosis of HCC was carried out by construc-ting receiver operaconstruc-ting characteristic (ROC) curves. The area under the ROC curve (AUROC) was deter-mined and compared in the different study groups.
In all cases, p ≤ 0.005 was taken as the threshold for statistical signifi cance.
The Ethics Committee and the Scientifi c Council from CIMEQ reviewed and approved the protocol for this investigation before its commencement.
R
esults
Table 1 shows the demographic and clinical charac-teristics of the 189 patients included in the study. Vi-ral hepatitis was the main cause of HC, with 83 ca-ses (43.92%). Hepatitis C virus (HCV) was the most frequent viral agent, being involved in 59 of these 83 cases; in addition, two of these patients were co infected with the hepatitis B virus (HBV), and other seven patients had problems with alcohol consump-tion. The second most common etiology was alcohol consumption, followed by cryptogenic cirrhosis, with 36 (19.05%) and 31 (16.40%) cases, respectively. The remaining causes (autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, se-condary biliary cirrhosis and Wilson’s disease) were grouped together as ‘other causes’, with 39 patients (20.63%).
Twenty-two patients were diagnosed with HCC (11.64%); they were predominantly male (male-fe-male ratio was 6.33). The main cause of HCC was viral HC, with 13 patients (59.09%), triggered mainly
Table 1. Patient demographics and clinical characteristics
Totals (n = 189, 100%) No HCC patients
(n = 167, 88.36%)
HCC patientsa
(n = 22, 11.64%) Sex
Age (years)
Male
Mean
Viral
HCVc
HBVd
HBV + HCV HCV + Alcohol
Alcoholic Cryptogenic Other causes
AIHe
PBCf
PSCg
SBCh
Wilson
aHCC: hepatocellular carcinoma.
bHC: hepatic cirrhosis. cHVC: hepatitis C virus. dHBV: hepatitis B virus. eAIH: autoimmune hepatitis. fPBC: primary biliary cirrhosis. gPSC: primary sclerosing cholangitis. hSBC: secondary biliary cirrhosis.
19 (86.36%)
55.00
101 (60.48%)
43.24
120 (63.49%)
44.61 69 (36.51%)
± 13.01 1.74
83 (43.92%) 50 24 2 7 36 (19.05%) 31 (16.40%) 39 (20.63%)
16 10 6 3 4
66 (39.52%)
± 12.54 1.53
70 (41.92%) 43 19 1 7 32 (19.16%) 26 (15.57%) 39 (23.35%)
16 10 6 3 4
3 (13.64%)
± 11.99 6.33
13 (59.09%) 7 5 1 0 4 (18.18%) 5 (22.73%) 0 (0%)
0 0 0 0 0
Female
Standard deviation
HC etiologyb
Male/Female
7. Ruoslahti E, Seppälä M. Studies of carcino-fetal proteins. 3. Development of a radioimmunoassay for alpha-fetoprotein. Demonstration of alpha-fetoprotein in serum of healthy human adults. Int J Canc. 1971;8:374-83.
8. Soresi M, Magliarisi C, Campagna P, Leto G, Bonfissuto G, Riili A, et al. Usefulness of alpha-fetoprotein in the diagnosis of hepatocellular carcinoma. Anticancer Res. 2003;23:1747-53.
9. Tong MJ, Blatt LM, Kao VW. Surveillance for hepatocellular carcinoma in patients with chronic viral hepatitis in the United States of America. J Gastroenterol Hepatol. 2001;16:553-9.
10. Collier J, Sherman M. Screening for hepatocellular carcinoma. Hepatology. 1998;27:273-8.
11. Bruix J, Sherman M, Llovet JM, Beau-grand M, Lencioni R, Burroughs AK, et al. Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL conference. European Associa-tion for the Study of the Liver. J Hepatol. 2001;35:421-30.
12. Gambarin-Gelwan M, Wolf DC, Shapiro R, Schwartz ME, Min AD. Sen-sitivity of commonly available screening tests in detecting hepatocellular carci-noma in cirrhotic patients undergoing liver transplantation. Am J Gastroenterol. 2000;95:1535-8.
by HCV infections (8 cases, one of them co-infected with HBV). The remaining etiologies for HCC in this group were alcoholic HC and cryptogenic cirrhosis, with four (18.18%) and fi ve (22.73%) patients respec-tively. The average age in this patient group was 55 ± 11.99 years (Table 1).
A total of 252 serum AFP determinations by the SUMA® methodology were performed during the
stu-dy, yielding a mean value of 16.43 ± 42.26 UI/mL. Table 2 shows the mean AFP values divided by HC etiology and age. It is evident that the levels were mar-kedly increased in patients with viral hepatitis (p < 0.001) and in patients with an age of 50 years or older (p = 0.001).
The only statistically signifi cant difference found in the multiple comparisons analysis (Table 3) was that of the mean AFP levels of patients with viral HC compared to patients whose etiology fell under the heading of ‘other causes’ (p < 0.001).
The levels of AFP in patients also suffering from HCC were higher than in the remaining patients (110.78 UI/mL vs. 7.40 UI/mL) (p < 0.001) (Table 4).
The sensitivity of AFP determinations for diagno-sing HCC was 68.18%; the specifi city values obtained were 92.17%; 45.45% for the PPV; and 96.80% for the NPV. Youden’s index was low, at 0.60 (Table 5).
The results for the diagnostic application of AFP in the case of HC, divided by etiology, are presented in Table 6. Youden’s index was low for all patient groups, with values of 0.58, 0.50 and 0.60 for viral HC, alcoholic HC and cryptogenic HC, respectively.
The fi gure shows the ROC curve of AFP when used to diagnose HCC. The area under the curve amounted to 0.846 (0.74-0.95). Table 7 presents the sensitivity, specifi city, and Youden’s index, according to the spe-cifi c diagnostic threshold chosen. Youden’s index was also low for each of these groups.
All patients underwent imagenological tests, which supported the HCC diagnosis established with the stu-dy criteria. The sensitivity, specifi city, PPV and NPV of abdominal sonography were 86.36%, 100%, 100% and 98.71% respectively to diagnose HCC. Youden’s index was very good (0.86). The combination of ab-dominal sonography and AFP increased sensitivity to 90.91% and NPV to 99.14%. Youden’s index, again, was excellent, at 0.91 (Table 8).
D
iscussion
Solid data on the real prevalence of HC worldwide is still lacking, and the available statistical fi gures are
always underestimated due to the high prevalence of undiagnosed cirrhoses. This situation is caused mainly by the fact that patients with compensated HC usually have no symptoms or conspicuous clinical signs of liver insuffi ciency and/or portal hypertension; in addi-tion, they may remain so far considerable periods of time [21].
Table 2. Average alpha-fetoprotein values in the study population, grouped by etiology and age
Etiology of the cirrhosis
Alpha-fetoproteina
Mean ± SDb p
Parameters
Viral hepatitis 26.48 ± 48.46 < 0.001
Alcohol 9.87 ± 36.89
Cryptogenic 14.08 ± 48.12
Other causes 2.30 ± 3.92
Age
aValues expressed in UI/mL. bSD: standard deviation.
≥ 50 years 30.41 ± 58.60 0.001
< 50 years 7.67 ± 23.87
Total 16.43 ± 42.26
Table 3. Multiple comparisons analysis for the mean levels of alpha-fetoprotein in the patients, according to the etiology
Etiology Mean difference (p)
Viral hepatitis Alcohol
Cryptogenic cirrhosis Other causes
Mean AFP*
26.48 9.87 14.08
2.30
- Other causes
24.175 (< 0.001) 7.563 (0.617) 11.780 (0.499)
-- Alcohol
16.612 (< 0.101)
-- Cryptogenic cirrhosis
12.395 (0.625) -4.216 (0.998)
-*AFP: Alpha-fetoprotein.
Table 4. Average alpha-fetoprotein values in patients with or without hepatocellular carcinoma
Alpha-fetoprotein
(Mean ± SDa)
n Hepatocelular
carcinoma
Yes 22
167 189
110.78 ± 86.17 7.40 ± 18.43 16.43 ± 42.26 No
Total
aSD: standard deviation.
Table 5. Performance of alpha-fetoprotein for the diagnosis of hepatocellular carcinoma
HCCa
Yes No Total
Alpha-fetoprotein
Positive
68.18 92.17 90.08 45.45 96.80 0.60 8.71 0.35
33 219 252
46.45 - 89.92 88.49 - 95.86 86.19 - 93.97 26.95 - 63.96 94.25 - 99.36 0.41 - 0.80 5.14 - 14.76
0.19 - 0.64 Negative
Total
Value CIb
Assay parameters
Sensitivity (%) Specificity (%) Validity index (%)
Positive predictive value (%)
Negative predictive value (%) Youden’s index
Verisimilitude ratio + Verisimilitude ratio
-aHCC: hepatocellular carcinoma. bCI: 95% confidence interval.
15 7 22
18 212 230
0 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0
0.1 0.2 0.3
1-Specificity
Sensitivity
0.4 0.5 0.6 0.7 0.8 0.9 1.0
Figure. Receiver operating characteristic curve for alpha-fetoprotein in the diagnosis of hepatocarcinoma. The black line corresponds to a 1:1 correlation between both parameters.
The etiology of HC, on the other hand, is better known. In developed countries, the causes of most HC cases are HCV infections and alcoholic liver disea-se [22], while in other parts of the world, such as the Asian Southeast and sub-Saharan Africa, HBV infec-tions constitute the main etiological agent [23].
The results of this study are conformed to our ex-pectations. Viral infections, mainly by HCV, and al-cohol consumption, were the fi rst and second most important etiologies for HC, respectively. This is the pattern typical of geographic areas where HBV infec-tion is not endemic [22]. The growing prevalence of HCV over HBV in Cuba constitutes the result of the sustained application of blood donor screening pro-grams and, most important, refl ects the impact of the National Vaccination Program against HBV, which began in 1991 with the administration of an effective HBV vaccine manufactured in the country (Heberbio-vac-HB®) to newborns from carrier mothers and was
later extended in 1992 to all newborns, together with the vaccination of the cohorts of children 8 and 14 years old from 1994 onwards [24].
HC has been known for a long time as the most im-portant risk factor for the development of HCC [25]. Independently from the etiology of HC, the risk of de-veloping HCC in these patients is estimated to range from 3 to 5% in a year [10, 26].
This investigation demonstrated the presence of HCC in 11.64% of the patients included in the study (Table 4). The principal causes of HCC, ordered by frequency, were the presence of viral HC (HCV-rela-ted mainly), the presence of cryptogenic cirrhosis, and the consumption of alcohol. These data are similar to those reported in countries with low prevalence and incidence rates of HBV [11, 27].
Although serum AFP levels have been shown to in-crease in association with several carcinomas, this pa-rameter has only been employed as a tumoral marker for HCC [28, 29]. The present investigation showed that serum AFP levels, measured with SUMA®
tech-nology, were signifi cantly higher in patients aged 50 years or older, in patients with viral HC, and in pa-tients with HCC.
The results coincide with previous reports investi-gating the infl uence of viral infections on AFP concen-trations. Increased levels of AFP are detected in viral hepatitis patients with no detectable HCC. Taking into account the results from different publications, it can be estimated that 10 to 43% of persons with a chronic HCV infection will have increases in this serum mar-ker [8, 30, 31]. Searching for an explanation to this fi n-ding, several studies have demonstrated a correlation
between increased serum AFP levels and the degree of infl ammation observed in liver biopsies [30-32].
The investigations examining the usefulness of AFP as a screening and surveillance tool have not been directly comparable: their design and the cha-racteristics of the studied population (type of viral in-fection, severity of liver disease, demographics) have differed. This fact alone explains the wide variability of their results, with sensitivities ranging from 41 to 69% and specifi cities between 75 and 94% [3, 9, 12, 16, 17, 20, 33-37].
A publication by Trevisiani et al. [3] has proposed that the best diagnostic threshold level for AFP ranges from 16 to 20 ng/mL. Using a threshold of 20 ng/mL, specifi city was indeed high (89.4%), but sensitivity was only 60%; this would produce such a signifi cant number of false negative diagnoses for a disease with the implications of HCC that the marker would not be useful for this purpose. Lowering the threshold iden-tifi es a larger number of cases, improving sensitivity at the price of an increased false positive rate. In other words, the higher the threshold, the lower the number of detected cases obtained (sensitivity decreases). A different study by Gambarin-Gelman et al. [12] also used an AFP diagnostic threshold of 20 ng/mL, and obtained a sensitivity of 58% and a specifi city of 91%. In exchange, PPV increased from 58 to 75% at higher levels of AFP (50 ng/mL), although it must be unders-cored that in the latter case, sensitivity dropped from 58 to 47%.
More recent results from Durazo et al. [33] and
El-Husseini et al. [34] using diagnostic thresholds of
19.8 and 25 ng/mL have reached the highest sensiti-vities reported so far in the literature (69 the former and 68.2% the latter). Specifi city in both studies was, however, discreetly lower.
The sensitivity and specifi city results obtained in this investigation for serum AFP measured with SUMA® technology can be considered good when
compared to the results summarized above. Using a diagnostic threshold of 15.38 UI/mL (equivalent to 19.07 ng/mL), sensitivity was 68.2%: a fi gure higher
Table 6. Assay parameters for alpha-fetoprotein when used to diagnose hepatocellular carcinoma, according to the etiology of the underlying cirrhosis
aCI: confidence interval.
Type of cirrhoses
Viral
Alcoholic
Cryptogenic
n
83
36
31
Sensitivity (CIa) 76.92%
50%
60% (50.17 - 100.00)
(0.00 - 100.00)
(7.06 - 100.00)
Specificity (CI)
81.25%
100%
100% (72.92 - 89.58)
(98.96 - 100.00)
(98.75 - 100.00)
Validity index (CI)
80.73% (72.87 - 88.60)
96.15% (89.97 - 100.00)
95.56% (88.42 - 100.00)
Positive predictive value (CI)
35.71% (16.18 - 55.25)
100%
100% (75.00 - 100.00)
(83.33 - 100.00)
Negative predictive value (IC)
96.30%
96%
95.24% (91.57 - 100.00)
(89.57 - 100.00)
(87.61 - 100.00)
Youden´s index
0.58 (0.10 - 077)
0.50 (0.01 - 0.99)
0.60 (0.17 - 1.03)
Table 7. Sensitivity, specificity and Youden’s index for different threshold values of alpha-fetoprotein in the diagnosis of hepatocellular carcinoma
*The normal reference value established at CIMEQ’s laboratory is 30 UI/mL.
Threshold* Sensitivity Specificity Youden’s index
15.38 UI/mL 68.2% 90.0% 0.582
31.50 UI/mL 68.2% 92.6% 0.608
50.37 UI/mL 68.2% 96.1% 0.643
91.71 UI/mL 54.5% 99.1% 0.536
172.5 UI/mL 45.5% 99.6% 0.451
15. Gebo KA, Chander G, Jenckes MW, Ghanem KG, Herlong HF, Torbenson MS, et al. Screening tests for hepatocellular carcinoma in patients with chronic hepatitis C: a systematic review. Hepatology. 2002; 36:S84-92.
16. Nguyen MH, Garcia RT, Simpson PW, Wright TL, Keeffe EB. Racial differences in effectiveness of α-fetoprotein for diagnosis of hepatocellular carcinoma in hepatitis C virus cirrhosis. Hepatology. 2002;36: 410-7.
17. Cedrone A, Covino M, Caturelli E, Pompili M, Lorenzelli G, Villani MR, et al. Utility of alpha-fetoprotein (AFP) in the screening of patients with virus-related chronic liver disease: does different viral etiology influence AFP levels in HCC? A study in 350 western patients. Hepatogas-troenterology. 2000;47:1654-8.
18. Daniele B, Bencivenga A, Megna AS,Tinessa V. Alpha-fetoprotein and ultra-sonography screening for hepatocellular carcinoma. Gastroenterology. 2004;127 (5 Suppl 1):S108-12.
19. Zinkin NT, Grall F, Bhaskar K, Out HH, Spentzos D, Kalmowitz B, et al. Serum pro-teomics and biomarkers in hepatocellular carcinoma and chronic liver disease. Clin Cancer Res. 2008;14(2):470-7.
20. Huo TI, Hsia CI, Chu CJ, Huang YH, Lui WY, Wu JC, et al. The predictive ability of serum α-fetoprotein for hepatocellular carcinoma is linked with the characteristics of the target population at surveillance. J Surg Oncol. 2007;95:645-51.
21. Schuppan D, Afdhal NH. Liver cirrosis. Lancet. 2008;371:838-51.
22. Mandayam S, Jamal M, Morgan TR. Epidemiology of alcoholic liver disease. Sem Liver Dis. 2004;24(3):217-32.
23. Marrero CR, Marrero JA. Viral hepatitis and hepatocellular carcinoma. Arch Med Res. 2007;38(6):612-20.
than the average of all the mentioned reports (60%) and similar to the two most recent ones. Specifi city, for this threshold, was also high, at 90%. This value also falls within the published range (78.3 to 94%).
It can be concluded that serum AFP levels of 91.71 UI/mL (113.72 ng/mL) or higher had diagnostic va-lue, with a specifi city higher than 99%. In short, less than 1% of the patients without HCC had AFP levels higher than 100 ng/mL. This is a better outcome than that reported by Nguyen et al. [16], who had a lower
specifi city (97.3%) at the same AFP threshold of 100 ng/mL and had to increase it to 200 ng/mL or higher to obtain a specifi city of 100%. In the report from Tre-visani et al. [3], levels higher than 200 ng/mL had a
specifi city of 99.4%.
Reviewing the evidence analyzed above, we su-pport the position stated by Gómez Senent et al. [38]
in a recent publication, arguing that the high specifi ci-ty that can be obtained with elevated diagnostic thres-holds for AFP allow its use as a confi rmatory test for HCC diagnosis.
The actual usefulness of sonography, as the sole diagnostic test, for the screening and surveillance of HCC in patients with HC is being increasingly con-tested, as a consequence of the absence of prospective studies and the widely varying sensitivity (35 to 84%) displayed by the technique. This variability has been ascribed not only to methodological differences in study populations, disease severity and non-uniform sampling frequencies, but also to susceptibilities to changes in tumor morphology, operator training and the quality of the measuring instrument [15, 39].
Regardless, abdominal sonography for HCC diag-nosis performed, in this study, at levels of sensitivity and specifi city much better than those presented in the preceding paragraph. Although we cannot reach a defi nitive conclusion regarding this result, it may be related to the characteristics of the tumoral lesions and the long experience of the personnel operating the ul-trasonographic equipment.
The diagnostic potential of the AFP/sonography combination has been examined before in other countries with good results. This combination aims, mainly, at simultaneously increasing both sensitivi-ty and specifi city for the diagnosis of HCC. Some authors refer that with this method sensitivity can even be taken to 100% [40]. In the present study, the combination of imagenology with serum AFP mea-surements by the SUMA® technology at a diagnostic
threshold of 15 UI/mL managed to increase sensitivi-ty and NPV to 90.91 and 99.14%, respectively; also increasing Youden’s index. The increase in sensitivi-ty, compared to sonography alone, is 5.7%. Values at the same order of sensitivity were reported by Kang
et al. [41].
No widely shared consensus has yet been reached concerning the combination of these tests, however; mainly due to the results of studies where the increa-ses in false positive rates and operational costs are also taken into account [42]. Yet, we consider that this is a useful and feasible strategy aimed at increasing the chances of obtaining a timely HCC diagnosis. The determination of serum AFP levels by Cuban SUMA®
technology is less costly that the remaining diagnos-tic techniques employed throughout the world, and in any case, proper training of the medical personnel is always paramount for an adequate interpretation of the results in each case.
The use of serum AFP determinations in the SUMA® technological platform was shown to
cons-titute a useful tool, with adequate sensitivity and spe-cifi city, for the diagnosis of HCC in cirrhotic patients. The combination of this assay with abdominal sono-graphy managed to increase the sensitivity and
speci-fi city of HCC diagnosis.
A
cknowledgements
We would like to express our gratitude to the resear-chers from the Immunoassay Center in Havana for their collaboration during the study.
Table 8. Paramaters for ultrasound, alone and in combination with alpha-fetoprotein, in the diagnosis of hepatocellular carcinoma
aCI: confidence interval.
bAFP: Alpha-fetoprotein; normal reference value of 15 UI/mL established by the laboratory.
Diagnosis
Ultrasound 86.36% (69.75 - 100)
90.91%
(76.62 - 100) (99.78 - 100)100% (97.91 - 100)99.21% (97.50 - 100)100% (97.73 - 100)99.14% (0.79 - 1.03)0.91
100%
(99.78 - 100) (97.27 - 100)98.81% (97.37 - 100)100% (97.05 - 100)98.71% (0.72 - 1.01)0.86%
+ AFPb
Ultrasound
Sensitivity
(CIa) Specificity(CI) index (CI)Validity Positive predicti-ve value (CI) Negative predic-tive value (CI) Youden’s index(CI)
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Received in April, 2010. Accepted
